This project of the Environmental Stress and Cancer Group investigates the molecular mechanisms of responses to environmental stresses involved in the etiology and progression of injury and disease processes. The overall goal of these studies is to provide a better understanding of the regulatory networks that control critical cellular responses to environmental stresses. Our approach utilizes advances in genomics and bioinformatics to address critical threats to human health as a consequence of environmental exposures. Specifically, the group is designing, executing, and analyzing studies that integrate global "omics" approaches with conventional studies of environmental stress, toxicity and disease processes. Core to these toxicogenomic efforts is the concept of phenotypic anchoring, in which studies are designed to relate alterations in gene expression to adverse effects defined by conventional parameters of toxicity and pathology. Studies are designed to provide insight into mechanisms of injury and disease as well as to establish signatures of adverse effects to develop putative biomarkers. These studies have utilized agents at multiple doses and times of treatment to fully explore ranges of biological responses to those agents. Analyses that implicate a critical role of a particular biological process or of a particular gene in an adverse response are followed up with additional experiments designed to test hypotheses concerning these roles. Studies have focused on the injury to the liver caused by exposures to a variety of hepatotoxic agents, including acetaminophen, and examined global gene expression changes in both the liver and circulating blood cells from rodents as well as blood cells from exposed humans for early indicators of the mechanism of injury as well as putative biomarkers. Additional studies have utilized a rodent model to investigate injury to the kidney specific to calcineurin-inhibitor (CI) immunosuppressants used clinically to prevent allograft rejection after organ transplantation. Microarrays have been utilized to examine injury mechanisms associated with CI toxicity and to look for gene expression changes that might give rise to clinically useful biomarkers of CI injury to the kidney.